Synthetic cannabinoids nano-micelles for the management of triple negative breast cancer

J Control Release. 2018 Dec 10:291:184-195. doi: 10.1016/j.jconrel.2018.10.030. Epub 2018 Oct 25.

Abstract

Triple-negative breast cancer (TNBC) is a highly heterogeneous disease with poor prognosis and inadequate therapeutic outcome. This contribution reports the use of a cannabinoid derivative, WIN55,212-2 (WIN) on the growth of TNBC in a 4T1 syngeneic mouse model. To reduce the well-known psychoactive side effects of cannabinoids, we prepared a nanomicellar formulation of WIN (SMA-WIN). In vivo biodistribution, in silico ADME predictions, anticancer activity, and psychoactive effect of WIN and SMA-WIN studies suggest that SMA-WIN formulation can reduce to greater extent tumor growth with milder psychoactive side effects when compared to free drug. Finally, the effects of WIN and SMA-WIN in combination with doxorubicin (Doxo), an established chemotherapeutic agent for the treatment of TNBC, were investigated in vitro and in vivo. SMA-WIN in combination with Doxo showed therapeutic efficacy and was able to reduce the tumor volume of TNBC murine model drastically. Moreover, SMA-WIN, while favoring drug tumor accumulation, minimized the adverse psychoactive effects that have impeded the use of this agent in the clinic. To our knowledge, this is the first report for the assessment of cannabinoid nanoparticles in vivo for the treatment of TNBC and its enhanced anticancer effect at low doses with Doxo. These findings suggest a new therapeutic strategy in the management of TNBC.

Keywords: 4T1; Breast tumor; Cannabinoids; Micelle; TNBC; WIN55,212-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / chemistry
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Benzoxazines / administration & dosage
  • Benzoxazines / chemistry
  • Benzoxazines / pharmacokinetics
  • Benzoxazines / therapeutic use*
  • Cannabinoids / administration & dosage
  • Cannabinoids / chemistry
  • Cannabinoids / pharmacokinetics
  • Cannabinoids / therapeutic use*
  • Cell Line, Tumor
  • Doxorubicin / administration & dosage
  • Doxorubicin / chemistry
  • Doxorubicin / pharmacokinetics
  • Doxorubicin / therapeutic use
  • Female
  • Humans
  • Mice, Inbred BALB C
  • Micelles*
  • Morpholines / administration & dosage
  • Morpholines / chemistry
  • Morpholines / pharmacokinetics
  • Morpholines / therapeutic use*
  • Naphthalenes / administration & dosage
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacokinetics
  • Naphthalenes / therapeutic use*
  • Tissue Distribution
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / pathology

Substances

  • Antineoplastic Agents
  • Benzoxazines
  • Cannabinoids
  • Micelles
  • Morpholines
  • Naphthalenes
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • Doxorubicin